Abstract
Chronic or non-healing skin wounds present an ongoing challenge in advanced wound care, particularly as the number of patients increases while technology aimed at stimulating wound healing in these cases remains inefficient. Mesenchymal stem cells (MSCs) have proved to be an attractive cell type for various cell therapies due to their ability to differentiate into various cell lineages, multiple donor tissue types, and relative resilience in ex-vivo expansion, as well as immunomodulatory effects during transplants. More recently, these cells have been targeted for use in strategies to improve chronic wound healing in patients with diabetic ulcers or other stasis wounds. Here, we outline several mechanisms by which MSCs can improve healing outcomes in these cases, including reducing tissue inflammation, inducing angiogenesis in the wound bed, and reducing scarring following the repair process. Approaches to extend MSC life span in implant sites are also examined.
Introduction
Wound healing is a complex multi-stage process that orchestrates the reconstitution of the dermal and epidermal layers of the skin. In many pathological circumstances such as diabetes or severe burns, the normal wound healing process fails to adequately restore function to the skin, leading to potentially severe complications from ulcers or resulting infections. As the incidence of obesity and resulting diabetes continues to increase in the western world,Citation1 the prevalence of chronic wounds related to these conditions continues to be a major focus of wound care research. In fact, non-healing wounds from these conditions have produced a multi-billion dollar advanced wound care market for technologies aimed at stimulating wound healing in patients that suffer from dysfunctional wound repair, with large projected growth in the near future.Citation2 Most current biological technologies for advanced wound care aim to provide antimicrobial support to the open wound and a matrix scaffold (collagen-based in many cases) for invading cells to reestablish the skin, with some focus on growth factor support of the healing process ().Citation8,Citation9 However, patient outcomes in this area remain marginal and novel bioengineered approaches to chronic wound repair remain a topic of high interest.
Table 1. Chronic wound healing technologies
Mesenchymal stem cells (MSCs) are important cells in orchestrating the three main phases of normal wound healing (inflammatory/proliferative/remodeling), directing inflammation and antimicrobial activity and promoting cell migration during epithelial remodeling.Citation10 However, recently due to advances in understanding of MSC immunosuppression and secretion of pro-angiogenic factors, MSC-based cell therapy in combination with matrix scaffold approaches to improve wound healing outcomes has become a potential strategy in treatment of non-healing wounds.
Traditionally, MSCs have long been identified for their ability to migrate to sites of injury in the body and differentiate into a variety of cell lineages such as bone, fat, and cartilage,Citation11-Citation14 making them attractive candidates for a variety of cell therapies in recent studies. A variety of easy means of isolating and expanding these cells ex-vivo (bone marrow,Citation15,Citation16 adipose tissue,Citation16,Citation17 placenta,Citation18 peripheral blood,Citation19 and others) also makes MSCs useful cells for therapeutic approaches to supplementing tissue regeneration (). Additionally, these cells have been shown to have notable immunomodulatory effects on the surrounding environment following transplantation,Citation29-Citation32 and can support native cells with the secretion of a variety of pro-survival and pro-migratory cytokines and growth factors.Citation33,Citation34 As a major problem in chronic wounding is unmitigated inflammation, this characteristic of MSCs has made them good candidates for approaches to cell therapy for chronic wounds in particular.
Table 2. Clinical sources of MSCs
In this review, we examine current trends in MSC therapy for chronic wound healing, including several major areas of MSC benefit to the wound repair process. Additionally, potential further MSC applications in wound healing and novel technologies are discussed.
Chronic Skin Wounds
The normal wound healing process is characterized by three main phases that lead to efficient reconstitution of a functional dermis/epidermis and revascularized tissue.Citation35,Citation36 Briefly, the inflammatory phase immediately follows wounding, serving to stop bleeding in the wound bed via platelet aggregation and fibrin clot formation. This is followed by invasion of neutrophils and mast cells that follow a chemotactic gradient to clear the wound of dead cells, debris, and residual ECM. The proliferative phase then proceeds, including fibroblast migration into the wound bed and deposition of new ECM (collagen). VEGF and B-FGF also stimulate de novo angiogenesis in the skin.Citation37-Citation39 Finally, the remodeling process resolves the wound by organizing collagen fibers that formed during fibroblast proliferation in parallel with further removal of fibronectin to increase the strength of the new skin.
A chronic or non-healing wound is essentially a wound that does not progress normally through the wound healing process, resulting in an open laceration of varying degrees of severity.Citation40,Citation41 These conditions can be cause by a number of various pathophysiological conditions (diabetes,Citation42 venous stasis ulcer progression,Citation43 and others), though all causes generally lead to a hyper-inflammatory environment, particularly evidenced by the characteristic presence of neutrophils/high MMP activity that leads to high breakdown of new collagen during the wound healing process and inhibition of pro-healing factors (PDGF, TGF-B, and others).Citation44-Citation47 This excessive inflammation phenotype leads to wounds that cannot resolve under normal circumstances, especially until the inflammation in the wound bed is controlled to a normal level and fibroblasts are able to effectively migrate into the wound space and synthesize new matrix.
Clinically, these wounds present a large problem for wound care specialists globally, with approximately 1–2% prevalence and a greater than 50% recurrence rate for diabetic patients.Citation48,Citation49 This need has generated a large interest in new treatments for improving patient outcomes in chronic wound therapies. Mesenchymal stem cells, given their immunomodulatory and angiogenic properties, have therefore been studied extensively with regards to cell therapy to supplement wound dressings. With over 350 listed clinical trials for MSC therapies (clinicaltrials.gov), many include studies utilizing MSCs for healing ischemic/diabetic foot ulcers and similar wounds ().
Table 3. Clinical trials for MSCs and chronic wounds
Ultimately, this interest in MSCs for cell therapies in wound healing revolves around several key aspects, including immunosuppression, angiogenesis stimulation, and scar reduction. As MSCs play a normal role in the wound healing process, they are an obvious candidate for study in this context as opposed to embryonic stem cells or other regenerative sources. Recent studies have outlined some successful approaches to promoting wound healing with MSCs, including autologous bone marrow-derived MSCs in fibrin matrixCitation52 or, more recently, intramuscular injection of autologous MSCs to improve diabetic wound closure.Citation54 While some trials have been aimed primarily at safety of MSC use for wound healing,Citation50 several clinical trials have shown the potential benefit of MSCs for inclusion in wound healing devices, including improved average rate of wound healing and general limb perfusion after treatmentCitation53 and also improved acute wound healing correlating to the number of injected cells.Citation52 Despite any effects on healing, there was some doubt as to any reduction in limb amputation rate or relative pain levels among groups, a major consideration for effective therapy in chronic wounds.Citation53 In general, the consensus from completed trials has been an overall improvement in chronic wound closure with application of mesenchymal stem cells, particularly as a part of a matrix delivery system (wound gel, etc.).
MSC Immunomodulation In Wound Beds
Chronic hyperinflammation in the wound bed is the most substantial barrier to treatment in non-healing wounds, as outlined previously. Mesenchymal stem cells have recently been shown to hold a variety of immunomodulatory effects on host immune cells in both wound healing and transplant biology contexts. These characteristics are potentially what make MSCs the most attractive cell type for cell therapy in chronic wounds, as they exert pleiotropic effects on the inflammatory mechanisms to move the wound past static inflammation and fibrosis.
It has been known for some time that donor MSCs are able to suppress host T cell proliferation, a key activity in reducing wound bed inflammation.Citation55 More recently, this was demonstrated to be dependent on MSC induction of IL-10Citation56 in native T cells and macrophages, as well as TGF-β activity.Citation57 Additionally MSCs have been shown to be capable of modulating host TNF-α production to mediate excessive inflammatory effects, and reduce NK cell function in the inflammatory phase, lowering IFN-γ activity in the process.Citation32 Conversely, in the later stages of inflammation, active TGF-α is able to stimulate implanted MSCs to produce a variety of pro-healing growth factors and cytokines, including VEGF to stimulate angiogenesis in the wound bed.Citation58 In 2008 Ren et al. showed a dependence on pro-inflammatory factors for these processes to be effective, suggesting a potential time window for application of allogeneic MSCs to be efficient in reducing inflammation.Citation59
Importantly, recent research into the immune response to allogeneic MSCs has shown that in most systems, the donor MSCs are ‘immunoprivileged’ and do not induce a significant response in the host, suggesting that allogeneic cell sources may be possible for chronic wound therapies, where diabetic patients may have already-defective endogenous MSC populations making autologous therapy less than optimal. This characteristic of allogeneic MSCs is crucial in this particular wound environment, where excessive inflammation already drives the chronic phenotype and additional immune response from cell implantation must be as low as possible. However, several studies have shown that this immunoprivileged characteristic is lost as the MSCs differentiate, leading to a gradual host response to the implanted cells.Citation60,Citation61 Thus, approaches to keeping MSCs undifferentiated may be key in future chronic wound therapies.
MSCs have also recently been identified as having antimicrobial effects, a significant advantage in reducing excess inflammation from any contaminants in the wound during injury and treatment.Citation62 This was identified in 2008 by Krasnodembskaya and colleaguesCitation63 as a mechanism based on secretion of LL-37, a peptide with a wide array of antimicrobial properties including broad spectrum microbial defense via disruption of bacterial cell membranesCitation64 and directly limiting bacterial macrophage activity via upregulation of chemokine receptors, all while ignoring pro-inflammatory cytokine activation.Citation65 In terms of cell therapeutics, the concern for reducing infection is great and many products attempt to seal wounds with silicone barriers to dressings. Silver nanoparticles have also been examined for antimicrobial properties, which can be conveniently included in wound healing gels and allowed to leach into the wound locally.Citation66,Citation67 Combined with MSC antimicrobial activity, this would help to reduce any additional inflammation seen during the healing process.
As a whole, all of the effects produced by MSCs here help to solve the problem of chronic hyperinflammation in the wound bed and advance wounds such as diabetic ulcers into the next stages of wound healing. Allogeneic application of MSCs in gel-based products for wound healing holds promise for combatting these issues, as has been done in various applications for MSC therapy using fibrin-based gel systemsCitation68,Citation69 and related mimetics.Citation70
Stimulation of Angiogenesis
Revascularization of the wound bed is a crucial stage of the normal wound healing process, where new vessels form as granulation tissue develops to supply blood to the wound area, which is in need of oxygen and nutrients. Endothelial cells therefore need to be able to break through the dermis of the wound and form tubes in the newly developing tissue, a process that is balanced by the growth factor production cascade during wound healing. Mesenchymal stem cells play a normal role in this process as they are recruited to the wound bed following mobilization from endogenous sources.Citation71,Citation72 The ability of mesenchymal stem cells to promote angiogenesis in vivo is not necessarily unique, as several other cell types have been shown to been integral in stimulating angiogenesis via cell therapy, such as hematopoietic stem cellsCitation73 or resident cardiac progenitor cells.Citation74 However, the unique role of MSCs during normal wound repair and additional effects of MSCs discussed in this review make the application of MSCs to stimulate vessel growth in chronic wounds particularly interesting for future studies in clinical MSC application for wound therapy.
There is evidence that MSCs can differentiate into a variety of skin cell types, contributing to repopulation of the wound bed with normal dermal structure, as well as endothelial cells to yield new vessels.Citation72,Citation75 Recently several groups have focused on differentiation of MSCs into endothelial cells, an approach that has potential to be useful in direct transplant into anti-angiogenic environments such as ischemic wound beds. Results have shown endothelial-like cell populations derived from human MSCs in vitro with varying degrees of donor variation,Citation76,Citation77 while Bago et al. showed similar results for amnion-derived MSCs in glioma tumors.Citation78 Furthermore, pericytes that stabilize vessel walls and promote vessel maturation during angiogenesis have been shown to be derived from bone marrow populations following injury.Citation79 Recent evidence suggests that these pericytes in fact represent a sub-population of mesenchymal stem cells that contribute to the healing process.Citation80 These cells all have the potential to support new vessel growth in a chronic wound bed, a critical aspect of overcoming barriers to current therapies.
Perhaps more important than differentiation, secreted factors also play a substantial role in MSC regulation of angiogenesis in the wound bed. Chronic wounds are often subject to anti-angiogenic conditions, including reduced growth factor production as a result of increased MMP production in the wound bed, as outlined by Krisp et al. recently in a global secretome analysis of wound exudates.Citation81 MSCs naturally produce a variety of pro-angiogenic factors following recruitment to the wound bed that stimulate endothelial cell proliferation and tube formation in the wound bed, most notably VEGF, a potent stimulator for angiogenesis that is regulated by IL-6 and TGF-α in the wound bed.Citation82 Though it has been shown that exogenous VEGF application to wounds can stimulate angiogenesis,Citation83 MSCs used in cell therapeutics also have been shown to stimulate EC recruitment and wound healing via VEGF secretionCitation33,Citation75 or via pre-differentiation into angiogenic precursors.Citation84 Ultimately, MSCs are able to stimulate de novo angiogenesis in wound beds upon transplantation, a crucial factor in stimulating healing in chronic wounds that lack this normally due to the hyperinflammatory environment.
Reduction in Scar Formation
Another consideration in repair of wounds under all circumstances is the formation of scars, caused by deposition of excess ECM by fibroblasts in the wound bed. These structures carry a variety of undesirable consequences, including unsightly appearance on the skin and, more critically, scars lack many of the normal makeup of the skin such as follicles and nerve endings and also do not retain the normal tensile strength of undamaged skin.Citation35 While scar reduction research has been a field in of itself for quite some time, it is a notable consideration for patients with large non-healing ulcers.
As discussed previously, anti-inflammatory mechanisms of MSCs have several effects on fibrotic phenotypes in the wound, and thus play a major role in reducing scar formation following wound healing. Most notably, MSC production of PGE2 drives a variety of changes in the scarring phenotype. PGE2 from MSCs has been shown to increase secretion of IL-10 by T cells and macrophages,Citation85 an important anti-inflammatory cytokine in the wound environment. PGE2 secreted by MSCs in response to the inflammatory wound bed plays a crucial role in the healing process, reducing T cell migration and NK cell proliferation during the inflammatory phase.Citation86,Citation87 The upregulation of IL-10 in the wound by MSCs also has a multitude of effects on general scar formation, including downregulation of IL-6 and IL-8 to reduce collagen production in the woundCitation88 and inhibition of neutrophil invasion and macrophage activity to suppress ROS generation,Citation89 all leading to support of regenerative healing in recent experimental scar formation models.Citation90 ROS generation is also affected by nitric oxide secreted by MSCs, acting as a scavenger to prevent the fibrotic activity of the oxygen radicals.Citation91,Citation92 Though these anti-inflammatory mechanisms are part of normal MSC function following homing to acute wound sites, the hyperinflammatory environment of a chronic wound makes the MSC ability to modulate excessive inflammation and reduce excessive scarring critical. Ultimately, reduced scar formation is not an outcome desired specifically for chronic wounds, but nevertheless is a significant potential benefit of utilizing MSCs to promote closure of such non-healing wounds. Experimentally, recent experimental evidence has shown that MSCs can indeed reduce a fibrotic phenotype in a mouse model,Citation93 showing promise for reduced scar formation in future MSC therapeutics.
Mesenchymal stem cells also produce a variety of anti-fibrotic factors throughout the wound healing process. Aside from IL-10, HGF is a major contributor to reduced fibrosis, which has been shown to be effective in advancing clean wound healing in a variety of tissues such as liverCitation94 and various skin contexts.Citation95,Citation96 HGF has also been attributed to chronic wounds, with differential regulation of HGF production and presence of c-Met in chronic wound dermis.Citation97 Specifically in relation to fibrosis, HGF has been demonstrated to reduce TGF-β and collagen production in fibroblasts,Citation98 and also have a multitude of effects on cell recruitment to the wound bed, including endothelial cells and promotion of keratinocyte migration.Citation99 Ultimately, HGF production by transplanted MSCs would yield a more normal state of cell migration and matrix production than what is normally seen in chronic wound beds.
Together in concert with the other immunomodulatory mechanisms of MSC function in wound repair, addition of MSCs to chronic wounds may prove to be an effective means of promoting cleaner healing on a smaller time scale than traditional treatments.
Promotion of MSC Survival
In typical cutaneous wound healing, MSCs are mobilized from host sources and home to the site of injury, persisting to support immunomodulation and improved angiogenesis in the wound bed as the skin repairs itself. These host MSCs are able to perform these normal functions despite somewhat challenging conditions in the wound site, such as hypoxia or lack of nutrients. However, in the case of chronic wounds, the normally-ischemic wound environment becomes even harsher, with excessive inflammationCitation100 and an environment not conducive to angiogenesis compared with normal wounds.Citation81 Therefore, a significant barrier to successful use of MSCs in any potential cell therapy has been post-implant cell survival in a variety of ischemic injury models. Past studies have shown marginal MSC preservation in various models including cardiac infarctCitation101 or cerebral injury,Citation102 but still MSC use in any of these models is limited by MSC death due to the harsh wound environment. As all of the benefits of MSC therapy for any type of wound healing are dependent on cell survival in the wound, strategies to improve survival following implantation are of interest in future research efforts. Recent studies have examined the effectiveness of preconditioning human MSCs with varying oxygen concentrations or pan-caspase inhibitors to improve the MSC survival response immediately following implantation. Saini et al. showed hyperoxic and pan-caspase pre-treatment of the cells substantially decreased MSC apoptosis in a cardiac infarct model, a scenario that produces an ischemic environment for implanted MSCs.Citation103 Conversely, Chang et al. recently demonstrated the advantages of preconditioning MSCs in hypoxia, which was shown to improve the secretory capabilities of the cells (VEGF, HGF, and others), a main benefit of MSC therapy.Citation104 Gene therapy in MSCs has also received some attention, as Wang et al. recently showed that adenoviral upregulation of protein kinase G1α improved MSC survival following implantation into a similar cardiac infarct model.Citation101
Additional recent studies have examined the possibility of exploiting endogenous signaling pathways in promoting MSC survival in a variety of wound healing contexts. The possibility of activating pro-survival pathways via matrikine moieties is a relatively novel concept that has been demonstrated to affect MSC signaling during wound healing normally.Citation105 This research led to the idea that EGFR could be activated by EGF molecules tethered to growth scaffolds, which was shown to improve MSC survival in vitro during cell death assays.Citation106,Citation107 This system of activating EGFR artificially to promote survival signaling has been applied to several tissue engineered surfaces, and provides the MSCs with a variety of survival advantages that could be used to combat the ischemic wound environment. More recently, Rodrigues et al. showed that the matrix protein Tenascin C could produce similar effects in vitro.Citation108 Tenascin is easily incorporated into collagen-based scaffolds, and could potentially be combined with current therapeutic gels to modulate MSC survival. This could be beneficial in scaffold design for MSC delivery to chronic wound beds, as biomaterials used in scaffold design can at times produce a more robust artificial inflammatory response.
Limitations of MSC Use in Chronic Wound Repair
As discussed in this article, one potential limitation to use of MSCs for treating chronic wounds is varying degrees of cell survival following implantation that might curtail any therapeutic effect in the long-term. However, there are other more fundamental hurdles to use of MSCs. One clear limitation to using MSCs as a standard therapy in any context is a general functional heterogeneity that makes a “standardized” MSC for manufacturing and quality control purposes a serious challenge. Changes in cell proliferation rate and differentiative capacity between donor sources have been reported for many years,Citation109 as well as functional differences among subpopulations of MSCs from a single source based on variation in RNA production.Citation110 Additionally, use of MSCs as therapeutic agents requires ex vivo expansion that, while somewhat more accessible than other stem cell types, can remain problematic due to the aforementioned heterogeneity as well as a very limited natural in vitro lifespan.Citation111 This all ultimately leads to issues in commercialization, where there remains no real set of guidelines for MSC expansion and general use in therapeutics for companies using the cells, despite their relatively common use in clinical trials and some marketed products.Citation112
Finally, the source of MSCs used can create a great deal of variation among therapeutic cells and also have an effect on harvesting methods. Many sources of MSCs have been discovered over time, including those mentioned in this article. There are complex and sometimes vast differences between MSCs obtained from bone marrow, adipose tissue, and other sources, ranging from cell surface marker expression to differentiation limitations and, importantly, immunomodulatory capacity (recently reviewed by Hass et al.Citation113). In terms of therapeutic strategy, this makes selection of a cell source an important consideration and/or limitation for any given therapy. For cutaneous wound healing, bone marrow-derived MSCs are the most often-used source, as evidenced by their inclusion in most of the clinical trials cited in this article (). However, adipose-derived cells and umbilical cord-derived cells have also been used for treating diabetic ulcers in clinical trials, suggesting continued disparity among researchers as to the optimal source.
Conclusions and Future Directions
Cell therapies for improving wound healing have become a topic of great interest, particularly for non-healing wounds such as diabetic or venous stasis ulcers. Patients with these wounds continue to be subject to inefficient wound care technologies that do nothing to stimulate the wound environment itself, instead providing secondary support via antimicrobial action or space filling matrix. Despite some potential limitations, we have here outlined several reasons why mesenchymal stem cells provide unique and effective support for stimulating the wound healing process in a chronic wound bed. Ultimately, these cells have the ability to suppress excessive inflammation and reduce scarring while stimulating de novo angiogenesis in the wound bed, all leading to promising outcomes in chronic wound repair.
Future directions for research in this field might focus on optimization of MSC function in chronic wound contexts, both in delivery systems and scaffold designs as well as improving cell survival via independent technologies or in combination with these delivery systems. The most promising current technologies, as outlined in several clinical trials cited in this review, include basic fibrin mesh scaffolds in gel form for seeding of MSCs; however, technologies for improving MSC efficiency in wound healing continue to emerge, such as recent studies for microsphere delivery in wound gel.Citation114 MSC therapy also holds promise in improving wound healing outcomes in other wound care settings, such as surgical wounds or burns.Citation115,Citation116 Ongoing studies into MSC immunomodulation and wound support in other wound models (myocardial infarction, brain, long bone defects, and others) may continue support advanced wound care research with insights into novel biomaterials and beneficial properties of MSCs in cell therapy.
Key Points
Chronic wound therapies present an ongoing problem in the advanced wound care sector with increasing prevalence of diabetes and related complications.
Mesenchymal stem cells provide a promising approach to healing these wounds.
MSC immunomodulation and related attenuation of scar formation are critical aspects of treating the hyperinflammatory chronic wound environment.
Cytokines produced from normal MSC function support angiogenesis in the healing wound.
Strategies to extend MSC survival and optimize cell delivery will improve these cell therapies in the future.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
The author would like to acknowledge the Wells lab at the University of Pittsburgh for support of ongoing translational research in mesenchymal stem cells and wound healing. He would also like to acknowledge Dr Alejandro Soto-Gutierrez for the opportunity to compile this review.
Funding
This article was funded by NIH T32EB001026.
Related Research Data
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